Heart valve disease falls into two major categories: acquired or congenital. In either case, the valve and/or the subvalvular apparatus is damaged. Damage of these structures can lead to valves becoming either incompetent or stenotic.
Incompetent valves suffer from degenerative changes leading to enlargement of the valve annulus. Enlargement of the annulus forces leaflets apart. As the leaflets get father apart, the leaflets do not meet properly, causing improper leaflet coaptation. This inability to close properly results in improper blood flow through the heat and eventually requires surgical correction either by valve repair or replacement.
Valve repair, also known as valvular annuloplasty, involves repairing the valve annulus by reinforcing the structure with a ring-shaped device or band fashioned from cloth materials. By properly sizing and installing the device, known as an annuloplasty ring, the surgeon can restore the valve annulus to its original, undilated circumference. This annular restoration will bring the leaflets back into correct alignment and restore valve competence.
Stenotic valves are valves in which the leaflets have lost their ability to move freely. Besides allowing for regurgitant flow across the valve, stenotic valves have a decrease in the valve orifice area. The decrease in orifice area creates large transvalvular pressure gradients. This condition forces the heart to work harder. The result is enlargement of the ventricles. Surgical procedures to correct such conditions require valve replacement.
Currently there are two types of prosthetic valves that can be used to replace failing valves: 1) mechanical and 2) bioprosthetic.
Mechanical valves are valves made on non-biological materials, consisting of a valve housing, a flow occluder, and a sewing ring. Bioprosthetic valves are composed of housing (known as a stent), a flow occluder (usually pericardium or aortic root tissue from animal sources that has been chemically preserved) and sewing ring. Like annuloplasty rings, mechanical and bioprosthetic valve sewing rings are composed of polyester cloth material constructed in either a knitted or woven configuration. The configuration of the cloth allows for cellular infiltration into the interstices of the fabric enabling the prosthesis to “heal in”. The “healing in” process creates a biological surface that is nonthrombogenic and acts as a barrier to transvalvular leaks.
Historically, polyester was chosen as the cloth material because of the healing response it elicited. Polyester was also chosen for its chemical inertness and resistance to enzymatic degradation. However, implantation of these nonresorbable materials permanently alters the microenvironment of the tissue where it is implanted. At the time of implantation the tissue of the valve annulus undergoes trauma from leaflet removal, dissecting away damaged and/or mineralized tissue, handling, sizing and suturing operations. The trauma results in the generation of a wound, with healing of the wound involving an inflammatory response. The nature and extent of the inflammatory response is dependent on the size of the wound bed as well as the nature of the material implanted into the wound. The result can be incomplete or improper healing.
In its simplest terms, the inflammatory response is divided into two phases, an acute phase and a chronic phase. Full details of the events of each phase are well documented by Shankar et al. (Chapter 5, “Inflammation and Biomaterials” in Implantation Biology, Host Response and Biomedical Devices, Ralph S. Greco, Ed., CRC Press, Inc., Boca Raton, Fla., 1994, 68-80). If the acute inflammatory response is not totally resolved it can progress to the chronic phase. The sequalae of events in the chronic inflammatory response can result in serious complications to valve function. Along with the deposition of inflammatory cells and the accumulation of cellular and proteinaceous blood elements, there is the formation of a fibrous sheath (of host origin) known as pannus. This fibrous tissue develops as an extension of the tissue healing the sewing ring. In the case of bioprosthetic tissue valves, if the inflammatory response is not resolved, the resulting pannus continues to grow, with the advancing fibrous tissue extending out onto the leaflets causing stenosis and/or incompetence. In addition to causing stenosis by inhibiting leaflet function, tissue overgrowth has been shown to cause leaflet retraction in pericardial valves, resulting in clinically significant regurgitation. Blood stasis or pooling is an other result of compromised leaflets. The progression of valve dysfunction in bioprosthesis is patient-dependent, and relates to how aggressive the patient's inflammatory response is to the implant. The progression of healing for mechanical valve recipients is similar to that observed with bioprosthetic but can have even more serious consequences. Tissue growth onto the valve can obstruct the occluder causing catastrophic failure of the valve. Thus, replacement valves, whether bioprosthetic or mechanical, often have shortcomings which may necessitate their removal. Because of the exuberant pannus growth into and onto the sewing ring of these valves, however, removal of the valves requires extensive dissection, making subsequent operations even more difficult.
Medical devices containing polymers are known to include therapeutic agents for delivery to surrounding tissue. For example, stents have been designed with polymeric coatings or films that incorporate a wide variety of therapeutic agents, such as anti-inflammatory agents, anti-thrombogenic agents, and anti-proliferative agents, for a wide variety of purposes. Antimicrobial compounds have been incorporated into polymeric portions of medical devices for sustained release to the surrounding tissue to enhance infection-resistance. Medical electrical leads have incorporated steroids into or at the lead tip electrode, to reduce source impedance and lower peak and chronic pacing thresholds. However, to date anti-inflammatory agents have not been recognized as useful for improving the biocompatibility and/or biostability of biomaterials used in implantable medical devices, particularly those that may need to be removed.
The polyester fabric typically used for manufacturing sewing rings of cardiac prosthetic valves, as well as annuloplasty rings and stent coverings, is thrombogenic and inflammatory in nature. It is known to activate complement and coagulation cascades, and has demonstrated a higher propensity for platelet deposition and thrombus formation prior to healing and tissue incorporation. It has been postulated that the thromboreactivity of the sewing ring material is the main culprit in the high incidences of thromboemboli related phenomena observed in the early postoperative period (T. Orszulak et al., 8th Annu. Meeting Eur. Assoc. Cardiacthoracic Surg. 1994:98; P. Perier et al., in E Bodner et al., Eds., Biologic and Bioprosthetic Valves, York Medical Books, 1986: 511-520).
There have been numerous attempts to treat polyester for the purpose of improving its function in vivo. Most have focused on reducing thromboreactivity of polyester in the hopes that the healing response would be accelerated, thereby preventing further contact with blood elements. Examples include: albumin impregnation, carbon coating, preclotting of the polyester fabric, cell seeding, synthetic peptide attachment, basic fibroblast growth factor (bFGF) attachment, fibrin coating containing bFGF and heparin, and polyurethane coating.
Ideally, medical implants should heal in well, without excessive tissue overgrowth, and allow for the establishment of a smooth neointimal transition between host and prosthesis. Reduction of the inflammatory response to porous materials such as polyester fabrics would be an important step toward complete healing of the surgical implant without the long term consequences of stenosis, regurgitation or catastrophic failure.
Many of the following lists of patents and nonpatent documents disclose information related to medical devices containing anti-inflammatory agents, particularly steroids. Others in the following lists relate inflammatory responses to polyester fabrics such as Dacron™; still others relate generally to biomaterials and human response mechanisms.
TABLE 1aPatentsU.S. Pat. No.Inventor(s)Issue Date4,506,680Stokes26 Mar. 19854,577,642Stokes25 Mar. 19864,585,652Miller et al.29 Apr. 19864,784,161Skalsky et al.15 Nov. 19884,873,308Coury et al.10 Oct. 19894,972,848Di Domenico et al.27 Nov. 19904,922,926Hirschberg et al.8 May 19905,002,067Berthelsen et al.26 Mar. 19915,009,229Grandjean et al.23 Apr. 19915,092,332Lee et al.3 Mar. 19925,103,837Weidlich et al.14 Apr. 19925,229,172Cahalan et al.20 Jul. 19935,265,608Lee et al.30 Nov. 19935,282,844Stokes et al.1 Feb. 19945,324,324Vachon et al.28 Jun. 19945,344,438Testerman et al.6 Sep. 19945,408,744Gates25 Apr. 19955,431,681Helland11 Jul. 19955,447,533Vachon et al.5 Sep. 19955,510,077Dinh et al.23 Apr. 19965,554,182Dinh et al.10 Sep. 19965,591,227Dinh et al.7 Jan. 19975,599,352Dinh et al.4 Feb. 19975,609,629Fearnot et al.11 Mar. 19975,679,400Tuch21 Oct. 19975,624,411Tuch29 Apr. 19975,727,555Chait17 Mar. 1998
TABLE 1bNonpatent DocumentsAckerman et al., “Purification of Human Monocytes on Microexudate-Coated Surfaces,” J. Immunol., 120, 1372-1374 (1978).Alderson et al., “A Simple Method of Lymphocyte Purification fromHuman Peripheral Blood,” J. Immunol. Methods, 11, 297-301 (1976).Anderson, “Mechanisms of Inflammation and Infection with ImplantedDevices,” Cardiovasc. Pathol., 2, 335-415 (1993).Anderson, “Inflammatory Response in Implants,” TASAIO, XXXIV, 101(1988).Boyum et al., “Density-Dependent Separation of White Blood Cells,”Blood Separation and Plasma Fractionation, 217-239, (eds) James Harris,Wiley-Liss, Inc. (1991).Bonfield et al., “Cytokine and Growth Factor Production by Monocytes/Macrophages on Protein Preadsorbed Polymers,” J. Biom. Mat. Res., 26,837-850 (1992.)Brais et al., “Acceleration of Tissue Ingrowth on Materials Implanted inthe Heart”, The Annals of Thoracic Surgery, 21, 221-229 (1976).Cardona et al., “TNF and IL-1 Generation by Human Monocytes inResponse to Biomaterials,” J. Biom. Mat. Res., 26, 851-859 (1992).Casas-Bejar et al., “In vitro Macrophage-Mediated Oxidation and StressCracking in a Polyetherurethane,” Transactions of the Fifth WorldBiomaterials Congress, Toronto, Canada, pg. 609 (1996).Cenni et al., “Platelet and coagulation factor variations induced in vitroby polyethylene terephthalate (Dacron ®) coated with pyrolytic carbon”,Biomaterials, 16, 973-976 (1995).French et al., “Rifampicin Antibiotic Impregnation of the St. Jude MedicalMechanical Valve Sewing Ring: A Weapon Against Endocarditis”, TheJournal of Thoracic and Cardiovascular Surgery, 112, 248-252 (1996).Fujimoto et al., “Ozone-Induced Graft Polymerization onto PolymerSurface,” J. Polym. Chem., 31, 1035-1043 (1993).Kadoba et al., “Experimental comparison of albumin-sealed and gelatin-sealed knitted Dacron conduits”, The Journal of Thoracic andCardiovascular Surgery, 103, 1059-1067 (1992).Kao et al., “Role of Interleukin-4 in Foreign-Body Giant Cell Formationon a Poly(etherurethane urea) in vivo,” J. Biomed. Mat. Res., 29,1267-1275 (1995).Karck et al., “Pretreatment of prosthetic valve sewing-ring with theantibiotic/fibrin sealant compound as prophylactic tool against prostheticvalve endocarditis”, Eur. J. Cardio-thorac Surg., 4, 142-146 (1990).Leake et al., “Comparative Study of the thromboresistance of Dacron ®combined with various polyurethanes”, Biomaterials, 10, 441-444 (1989).Marchant et al., “In vivo Biocompatibility Studies. I. The Cage ImplantSystem and a Biodegradable Hydrogel,” J. Biomed. Mat. Res., 17, 301-325 (1983).Miller et al., “Generation of IL1-like activity in response to biomedicalpolymer implants: A comparison of in vitro and in vivo methods”, J. ofBiomed. Mat. Res., 23, 1007-1026 (1989).Miller et al., “Human Monocyte/Macrophage Activation and Interleukin-1Generation by Biomedical Polymers,” J. Biom. Mat. Res., 22, 713-731(1988).Mond et al., “The Steroid-Eluting Electrode: A 10-Year Experience,”PACE, 19, 1016-1020 (1996).Onuki et al., “Accelerated Endothelialization Model for the Study ofDacron Graft Healing”, Annals of Vascular Surgery, 11, 141-148 (1997).Orszulak et al., “The risk of stroke in the early postoperative periodfollowing mitral valve replacement”, European Journal of CardiothorasicSurgery, 9, 615-620 (1995).Perier et al, “Comparison of thromboembolic an anticoagulant-relatedcomplications after aortic valve replacement using Starr Edwards, Bjork-Shiley and porcine valve prostheses”, Bodnar E. Yacoub M (eds).Biologic and Bioprosthetic Valves: York Medical Books, 511-520 (1986).Rubin et al., “Preincubation of Dacron grafts with recombinant tissuefactor pathway inhibitor decreases their thrombogenicity in vivo”, J.Vasc. Surg., 24, 865-870 (1996).Schubert et al., “Oxidative Biodegradation Mechanisms of BiaxiallyStrained Poly(etherurethane urea) Elastomers,” J. Biomed. Mat. Res.,29, 337-347 (1995).Schwartz et al., “Local anticoagulation of prosthetic heart valves”,Circulation, 43 (Suppl. III), 85-89 (1973).Shanbhag et al., “Macrophage/Particle Interactions: Effects of Size,Composition and Surface Area,” J. Biomed. Mater. Res., 28, 81-90(1994).Shankar et al., “Chapter 5: Inflammation and Biomaterials”, ImplantationBiology. Host Response and Biomedical Devices, (eds) Ralph S. Greco,CRC Press, Inc., Boca Raton, FL 67-80 (1994).Stokes et al., “Polyurethane Elastomer Biostability,” J. of BiomaterialsApplications, 9, 321-354 (1995).Takahashi, “Adsorption of Basic Fibroblast Growth Factor onto DacronVascular Prosthesis and Its Biological Efficacy”, Artif Organs, 21, 1041-1046 (1997).Tweden et al., “Accelerated Healing of Cardiovascular Textiles Promotedby an RGD Peptide”, J. Heart Valve Dis, 4 (Suppl. I), S90-97 (1995).Van Der Lei et al., “Improved healing of small-caliber polytetrafluoro-ethylene prostheses by induction of a clot layer: a review of experimentalstudies in rats”, International Angiology 10, 202-208 (1991).Wilkerson et al., “Biomaterials Used in Peripheral Vascular Surgery” (eds)Ralph S. Greco, CRC Press Inc., Implantation Biology: The HostResponses and Biomedical Devices, 179-190 (1994).Zhao et al., “Cellular Interactions and Biomaterials: In vivo Cracking ofPre-stressed Pellethane 2363-80A,” J. Biom. Mat. Res., 24, 621-637(1990).Zhao et al., “Glass Wool-H2O2/CoCl2 Test System for In Vitro Evaluationof Biodegradative Stress Cracking in Polyurethane Elastomers,” J.Biomed. Mat. Res., 29, 467-475 (1995).
All patent and nonpatent documents listed in Table 1 are hereby incorporated by reference herein in their respective entireties. Citation and incorporation by reference of these documents is not, however, to be construed as an admission that any or all of the documents are prior art as to the present invention. As those of ordinary skill in the art will appreciate upon reading the Summary of the Invention, Detailed Description of the Invention, and Claims set forth below, many of the devices and methods disclosed in these documents may be modified advantageously by using the teachings of the present invention.